ORIGINAL ARTICLE Quantitative Brain Magnetic Resonance Imaging in Girls With Attention-Deficit/Hyperactivity Disorder F. Xavier Castellanos, MD; Jay N. Giedd, MD; Patrick C. Berquin, MD; James M. Walter, MA; Wendy Sharp, MSW; Thanhlan Tran, BS; A. Catherine Vaituzis; Jonathan D. Blumenthal, MA; Jean Nelson, MHS; Theresa M. Bastain, BA; Alex Zijdenbos, PhD; Alan C. Evans, PhD; Judith L. Rapoport, MD Background: Anatomic studies of boys with attention- Results: Total brain volume was smaller in girls with ADHD deficit/hyperactivity disorder (ADHD) have detected de- than in control subjects (effect size, 0.40; P=.05). As in our creased volumes in total and frontal brain, basal gan- previous study in boys with ADHD, girls with ADHD had glia, and cerebellar vermis. We tested these findings in a significantly smaller volumes in the posterior-inferior cer- sample of girls with ADHD. ebellar vermis (lobules VIII-X; effect size, 0.54; P=.04), even when adjusted for total cerebral volume and vocabulary Methods: Anatomic brain magnetic resonance images score. Patients and controls did not differ in asymmetry in from 50 girls with ADHD, of severity comparable with any region. Morphometric differences correlated signifi- that in previously studied boys, and 50 healthy female cantly with several ratings of ADHD severity and were not control subjects, aged 5 to 15 years, were obtained with predicted by past or present stimulant drug exposure. a 1.5-T scanner with contiguous 2-mm coronal slices and 1.5-mm axial slices. We measured volumes of total ce- Conclusions: These results confirm previous findings rebrum, frontal lobes, caudate nucleus, globus pallidus, for boys in the posterior-inferior lobules of the cerebel- cerebellum, and cerebellar vermis. Behavioral measures lar vermis. The influence of the cerebellar vermis on pre- included structured psychiatric interviews, parent and frontal and striatal circuitry should be explored. teacher ratings, and the Wechsler vocabulary and block design subtests. Arch Gen Psychiatry. 2001;58:289-295 NVESTIGATIONS of attention- caudate nucleus volume or asymmetry deficit/hyperactivity disorder have been found by every group that has (ADHD) with the use of mag- examined ADHD samples,2,3,10,11 making netic resonance (MR) imaging this sexual dimorphism particularly in- implicate dysfunction of prefron- teresting in a study of girls with ADHD. tal cortical-striatal-pallidal circuitry1-6 and Studying girls with ADHD raises ques- I 7,8 of the cerebellar vermis. Although there tions regarding severity and diagnostic va- has been substantial convergence of re- lidity,15,16 which we addressed by recruit- sults,9 some inconsistencies remain. For ing girls with ADHD in whom severity and example, most studies have reported de- phenomenologic characteristics were com- creased caudate volume in ADHD, but lat- parable with those of our previously stud- erality has varied,2,3,10,11 and one study ied boys with ADHD.17 We now report, to found larger caudate area in adolescents our knowledge, the first anatomic brain MR with ADHD.11 imaging study of female patients with From the Child Psychiatry Of the patients described in the ana- ADHD. Our hypothesis was that prefrontal- Branch, National Institute of tomic studies cited above, 92% were male, striatal-pallidal and cerebellar abnormali- Mental Health, Bethesda, Md reflecting in part the male preponder- ties similar to those noted in boys with (Drs Castellanos, Giedd, and ance in the disorder.12 Combining males ADHD2,7 would be observed in girls. Rapoport, Messrs Walter and and females (as has sometimes been Blumenthal, and Mss Sharp, 10,11 done ) is problematic because there are RESULTS Tran, Vaituzis, Nelson, and robust (approximately 10%) male- Bastain); Service de Pe´diatrie 1, female differences in overall brain vol- CHU Hoˆpital Nord, Amiens, SUBJECTS France (Dr Berquin); and ume. Most regional brain volumes are also Montreal Neurological approximately 10% smaller in females, but Table 1 presents patient and control char- Institute, McGill University, there are important exceptions, such as the acteristics. There were no significant group Montreal, Quebec caudate nucleus, which is proportion- differences in age, height, weight, Tan- (Drs Zijdenbos and Evans). ately larger in females.13,14 Differences in ner pubertal stage, handedness, or WISC-R (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 58, MAR 2001 WWW.ARCHGENPSYCHIATRY.COM 289 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 SUBJECTS AND METHODS and neurologic examinations, the 12 handedness items from the Revised Physical and Neurological Examination for Subtle 31 Subjects With ADHD Signs, structured psychiatric interview using the Diag- nostic Interview for Children and Adolescents,20 Child Be- 21 Girls with combined-type ADHD (meeting both hyperac- havior Checklist, the WISC-R (n=24) or WISC-III (n=16) vocabulary and block design tests, and Wide Range Achieve- tivity-impulsivity and inattention criteria) (n=50; mean age, 32 9.7 years; range, 5.3-16.0 years) were recruited for Na- ment Test, Revised Edition. Family psychiatric history for tional Institute of Mental Health ADHD drug treatment stud- first- and second-degree relatives was ascertained from 1 or ies17 within a specialized day program (n=36) or specifi- both parents. Individuals with physical, neurologic, or life- cally for this imaging study (n=14). Inclusion criteria were time history of psychiatric abnormalities, or who had any first- hyperactive, inattentive, and impulsive behaviors that were degree relatives or greater than 20% of second-degree rela- impairing in at least 2 settings (home, school, or day pro- tives with major psychiatric disorders, were excluded. gram), and a Conners’ Teacher Hyperactivity rating greater Approximately 4 candidates were screened for every 1 ac- than 2 SDs above age mean.18 The DSM-IV19 diagnosis of cepted, with the most common exclusions being family psy- ADHD was based on the Diagnostic Interview for Chil- chiatric history and possible psychiatric diagnosis based on dren and Adolescents,20 with a parent and separately with structured interview or teacher report. the patient if she was older than 9 years; Conners Teacher Assent from the child and written consent from the Rating Scale18; and the Teacher Report Form.21 The Wech- parents were obtained. The National Institute of Mental sler Intelligence Scale for Children–Revised (WISC-R)22 was Health institutional review board approved the protocol. used for 32 patients and the Wechsler Intelligence Scale for Children–Third Edition (WISC-III)23 for 17 (1 missing). BEHAVIORAL MEASURES To allow comparison with our previous studies of boys, WISC-III full-scale, vocabulary, and block design subs- Patients underwent a psychoeducational evaluation (full cale scores were converted to WISC-R equivalents on the WISC-R and Woodcock-Johnson Psychoeducational Test Bat- basis of published data.24-27 tery–Revised) by a clinical psychologist (Barbara Keller, PhD) during medication-free baseline. The hyperactivity factor, ex- Thirty-five patients (70%) had been previously 18,33 treated with stimulants, as determined from parental tracted from the Conners’ Parent and Teacher Rating Scales, reports. Measures of stimulant drug exposure were life- was averaged from the 3 weekly placebo ratings, as were phy- sician ratings on the Children’s Global Assessment Scale34 and time exposure (yes or no), current daily dose in methyl- 35 phenidate hydrochloride equivalents at the time of scan- Clinical Global Impressions scale for severity of illness. Base- ning (1 mg of amphetamine sulfate=2 mg of line ratings were substituted for patients who did not par- ticipate in medication trials (n=14). Parents also provided methylphenidate hydrochloride), and estimated cumula- 21 tive lifetime methylphenidate equivalent dose calculated ratings on the Child Behavior Checklist. from parental reports. Exclusion criteria were a full-scale WISC-R IQ less than MR IMAGE ACQUISITION 80, evidence of medical or neurologic disorders on exami- nation or by history, Tourette disorder, or any other Axis All subjects were studied on the same 1.5-T scanner (Signa; I psychiatric disorder requiring treatment with med- General Electric Co, Milwaukee, Wis). T1-weighted im- ication. Thirteen subjects met lifetime criteria for mild ages with contiguous 1.5-mm slices in the axial plane and anxiety or mood disorders, and 5 had reading disorder con- 2.0-mm slices in the coronal plane were obtained by means firmed by discrepancy (z.1.65) between Woodcock- of 3-dimensional spoiled gradient recalled echo in the steady Johnson Psychoeducational Test Battery and WISC-R stan- state. Imaging variables were as follows: echo time, 5 mil- dard scores.28,29 Other demographic and diagnostic liseconds; repetition time, 24 milliseconds; flip angle, 45°; 3 characteristics are included in Table 1. acquisition matrix, 256 192; number of excitations, 1; and field of view, 24 cm. Vitamin E capsules, wrapped in gauze Normal Control Subjects and placed in each auditory meatus, were used to stan- dardize head placement. A third capsule was taped to the Unrelated healthy girls (n=50; mean age, 10.0 years; range, lateral aspect of the left inferior orbital ridge. The capsules 4.7-15.9 years) were recruited from the community. Screen- are readily identifiable on MR images and were used to de- ing included telephone interview, parent and teacher rating fine a reference plane and to verify